A series of 6-phenylpurine based hydroxamates have been designed, synthesized and evaluated. Compound 3b and its analogs are potent histone deacetylase (HDAC) but weak PI3K/mTOR inhibitors. These compounds demonstrated broad anti-cancer activities against 38 cancer cell lines with leukemia, lymphoma, and the majority of liver cancer cell lines exhibiting the most sensitivity towards these compounds. Compound 3b demonstrated modulation of HDAC targets in vitro in a dose-dependent manner. It has good in vitro ADME profile that translated into a greatly improved pharmacokinetic profile. 3b also demonstrated modulation of HDACs in tumors in a PC-3 xenograft model. It was further evaluated in combination therapies in vitro. It exhibited additive or synergistic growth inhibition effect in HepG2 cells when combined with a number of approved drugs such as sorafenib, sunitinib, and erlotinib. Hence, 3b has the potential to be combined with the above to treat advanced liver cancer. As such, current data warrant further evaluation, optimization, and subsequent in vivo validation of the potential combination therapies. Selective JAK3 inhibitors have been shown to have a potential benefit in the treatment of autoimmune disorders. Here we report the identification of a series of pyrazolopyrimidine derivatives as potent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Most of these compounds (13k, 13n and 13&nbsp;t), displayed stronger anti-JAK3 kinase activity and selectivity than tofacitinib. Furthermore, the most active inhibitor 13t (IC50&nbsp;=&nbsp;0.1&nbsp;nM), also exhibited favourable selectivity for JAK3 in a panel of 9 kinases which contain the same cysteine. In a series of cytokinestimulated cellular analysis, compound 13&nbsp;t, could potently block the JAK3-STAT signaling pathway. Further biological studies, including cellular antiproliferative activity assays and a rat adjuvant-induced arthritis model for in vivo evaluation, also indicated its efficacy and low toxicity in the treatment of rheumatoid arthritis. The results of these experimental explorations suggested that 13t is a promising lead compound for the development of selective JAK3 inhibitor with therapeutic potential in rheumatoid arthritis. BACKGROUND AND AIMS The endothelium is crucially involved in the pathogenesis of atherosclerosis according to accumulating evidence. Moreover, recent studies have showed that lncRNAs could serve as biomarkers of cardiovascular diseases, in particular atherosclerosis. However, the underlying mechanism of endothelial dysfunction involving lncRNAs in atherosclerosis remains unknown. This study investigated the mechanism of lncRNA XXYLT1-AS2 in endothelial dysfunction in atherosclerosis. METHODS The levels of lncRNA XXYLT1-AS2, FUS, VCAM-1, MCP-1, p-AKT, and p-P65 were measured in arteries and HUVEC cell lines via quantitative real-time PCR or Western blot. FISH assay demonstrated that XXYLT1-AS2 and FUS are localized in the nucleus. HUVECs were transfected with si-XXYLT1-AS2 or XXYLT1-AS2 to further assess cell proliferation, migration, and adhesion. Furthermore, bioinformatics analysis, RNA immunoprecipitation and immunofluorescence were performed to investigate the target genes of XXYLT1-AS2 and possible signal pathways. RESULTS Overexpression of XXYLT1-AS2 inhibited cell proliferation and migration, reduced the expression of adhesion molecules (VCAM-1) and chemoattractant proteins (MCP-1), and restrained monocyte adhesion to endothelial cells. Mechanistic investigations indicated that XXYLT1-AS2 directly interacts with the target gene FUS/cyclin D1 and modulates the proliferation and migration of endothelial cells (ECs). Moreover, XXYLT1-AS2 exerts a protective role against the inflammatory response in atherosclerosis by blocking NF-κB activity. Clinically, the involvement of XXYLT1-AS2/FUS was also observed in human arteries and the results were consistent with the in vitro analysis. CONCLUSIONS Our study identified a novel long non-coding RNA (XXYLT1-AS2) and suggests that it might act as an underlying therapeutic target in atherosclerosis-related diseases by regulating ECs functions. BACKGROUND AND AIMS Familial hypercholesterolaemia (FH) is characterised by a high, but variable risk of premature coronary artery disease (CAD). Cardiac computed tomography angiography (CCTA) can be employed to assess subclinical coronary atherosclerosis. We investigated the features and distribution of coronary artery plaques in asymptomatic patients with and without genetically confirmed heterozygous FH. METHODS We undertook an aged-matched case-control study of asymptomatic phenotypic FH patients with (cases, M+) and without (controls, M-) an FH-causing mutation. Coronary atherosclerosis was assessed by CCTA and calcium scoring. https://www.selleckchem.com/products/brefeldin-a.html Coronary segments were evaluated for global and vessel-level coronary plaques and degree of stenosis. RESULTS We studied 104 cases and 104 controls (mean age 49.9&nbsp;±&nbsp;10.4 years), who had a similar spectrum of non-cardiovascular risk factors. Pre-treatment plasma LDL-cholesterol was higher in the M+ than M-&nbsp;group (7.8&nbsp;±&nbsp;2.1 vs 6.2&nbsp;±&nbsp;1.2&nbsp;mmol/L, p less then 0.001). There was a greater proportion of patients with mixed and calcified plaque, as well as a higher coronary artery calcium score and segment stenosis score (all p less then 0.05), in the M+ compared with the M-&nbsp;group. M+ patients also had a significantly higher frequency of coronary artery calcium in the left main and anterior descending and right coronary arteries (all p less then 0.05), but not in the left circumflex. CONCLUSIONS Among patients with phenotypic FH, those with a genetically confirmed diagnosis had a higher frequency and severity of coronary atherosclerotic plaques, and specifically more advanced calcified plaques. BACKGROUND AND AIMS Patients with overnutrition, obesity, the atherometabolic syndrome, and type 2 diabetes typically develop fatty liver, atherogenic dyslipoproteinemia, hyperglycemia, and hypertension. These features share an unexplained origin - namely, imbalanced insulin action, also called pathway-selective insulin resistance and responsiveness. To control glycemia, these patients require hyperinsulinemia that then overdrives ERK and hepatic de-novo lipogenesis. We previously reported that NADPH oxidase-4 regulates balanced insulin action, but the model appeared incomplete. METHODS We conducted structure-function studies in liver cells to search for additional molecular mediators of balanced insulin action. RESULTS We found that NADPH oxidase-4 is part of a new limb of insulin signaling that we abbreviate "NSAPP" after its five major proteins. The NSAPP pathway is an oxide transport chain that begins when insulin stimulates NADPH oxidase-4 to generate superoxide (O2?-). NADPH oxidase-4 forms a novel, tight complex with superoxide dismutase-3, to efficiently transfer O2?- for quantitative conversion into hydrogen peroxide.